Serum cobalamin assay is the usual clinical means of diagnosing cobalamin deficiency. However, low serum levels of this vitamin occur in patients without obvious deficiency, and this problem has greatly increased in frequency recently. Low serum levels now are more commonly due to this phenomenon than to true cobalamin deficiency. Since none of the overt clinical stigmata of cobalamin deficiency accompany it, this phenomenon, which occurs particularly frequently among the elderly, has been assumed to be completely benign. However, studies to date have not examined it in detail and its nature remains obscure. We propose to investigate carefully such patients with seemingly falsely low serum cobalamin levels. We will assess the cases in detail clinically, hematologically and neurologically. These studies will be augmented by specialized techniques to detect subtle defects of cobalamin status, using biochemical assessment of DNA synthesis by marrow cells and the effects of specific additives in vitro. Other studies will be assay of urinary metabolic intermediate excretion, electrophysiologic assessment of neurological status, studies of cobalamin transport in the circulation, and tests for subtle malabsorption of cobalamin. These studies are aimed at addressing the clinical questions posed and at testing several hypotheses about cobalamin metabolism, transport and absorption. The answers should provide a sound scientific basis for the management of the clinical problems posed by the phenomenon in question. They should also expand our appreciation of the range of subtle states of cobalamin insufficiency and enhance our understanding of cobalamin physiology and pathology.